In this longitudinal cohort study, patients with DM2 and HIV infection who initiated diabetic medical therapy achieved smaller absolute reductions in HbA1c than patients with DM2 and no HIV infection in the course of routine clinical care. This less robust response was more pronounced in HIV-infected patients on a PI-based regimen compared to those on a non-PI-based regimen, and was independent of several important potentially confounding factors including the baseline HbA1c level.
Overall, the entire cohort of new-users, who were almost exclusively treated with monotherapy and predominantly with metformin, achieved an absolute reduction in HbA1c of approximately 1% after initiation of pharmacologic therapy. This response is consistent with that reported in studies in the HIV-uninfected population after one year of oral monotherapy [37
]. Notably, HIV-infected patients in our study had lower HbA1c values compared to HIV-uninfected patients at baseline and all time points through the year after initiation of therapy. Several studies suggest that HbA1c may underestimate glycemic control in HIV-infected patients [40
], and this HbA1c-glucose discordance may in part be explained by hemolysis and use of specific ART agents. Nevertheless, in the present study, HIV-infected patients, even after adjustment for baseline HbA1c, achieved significantly smaller reductions in HbA1c compared to patients without HIV infection. While the mechanisms behind this association are unclear, our subanalyses, based on a limited number of patients, suggest that decreased responses in those with HIV are more pronounced in users of PIs. This finding is consistent with data indicating increased insulin resistance in recipients of PIs [3
] and use of these medications, particularly in individuals with uncontrolled DM2 and HIV, should be carefully considered when weighing treatment options. The observed differences in glycemic response may also relate in part to persistent inflammation or immune activation, which have been associated with both HIV infection and insulin resistance [26
]. Although our subanalyses did not support this mechanism, CD4+ T-cell count and viral load, while associated with inflammation and immune activation, are only approximate measures of these underlying processes [26
] and future investigations of this issue should characterize these parameters more directly. In particular, insulin resistance itself has been strongly associated with inflammation [44
] and future studies should aim to measure levels of inflammatory biomarkers (e.g., C-reactive protein) as well as markers of immune activation.
The rate of achievement of a HbA1c <7% in our study was 72.7% for HIV-infected patients. To our knowledge, there are currently only three studies in the literature evaluating achievement of a HbA1c <7% in HIV-infected patients, all of which reported rates of approximately 50% [47
]. However, these studies were cross-sectional reports of patients with prevalent DM2 and therefore are not comparable to our cohort of new-users. Furthermore, HbA1c-glucose discordance [40
] may in part explain why HIV-infected patients, despite smaller absolute reductions in HbA1c, were more likely to achieve the ADA goal. Nonetheless, although the absolute difference in HbA1c was modest and HIV-infected patients were more likely to achieve goal HbA1c values, studies in the HIV-uninfected literature have demonstrated that even a small reduction in HbA1c of ~0.8% significantly reduces the risk of microvascular and macrovascular complications [50
]. Given this less robust glycemic response to standard medical therapy for DM2, it will be important for HIV providers to focus on aggressive, timely management of glycemia as well as achievement of recommended lipid and blood pressure goals to reduce associated morbidity and mortality. The finding that HIV-infected patients who started with higher baseline HbA1c values (>8%) in our study had an even more pronounced poorer response to initial therapy provides further justification for early and prompt initiation of treatment in patients with recently diagnosed DM2.
To our knowledge, the present study is the first in the literature to evaluate the response to initial diabetic medical therapy in patients with HIV infection compared to those without HIV infection. The results are strengthened by the large size of our cohort, capture of comprehensive clinical data for assessment of confounding, and evaluation of HIV-specific, mechanistic factors such as ART regimen and virologic control that could arguably affect glycemic response. Finally, the present study evaluated patients receiving routine medical care, thereby measuring the impact of medications in a “real-world” clinical setting as opposed to the more artificial setting of a clinical trial where patients are highly selected for inclusion.
There are also several potential limitations of the present study. As with any observational study, our results may be affected by confounding. However, we attempted to account for a wide variety of relevant factors in our multivariable analysis, employed a new-user design which minimizes prevalent-user bias, and used a longitudinal model which permitted incorporation of all follow-up HbA1c results in the analyses. Furthermore, we were unable to ascertain data on adherence to diabetic medical therapy; however, we evaluated comorbid conditions that could potentially affect adherence in our analyses, and there were minimal therapy switches in both patient groups, thereby suggesting low rates of adverse medication effects that could lead to poor adherence. The use of separate cohorts for patients with and without HIV infection is another potential limitation; however, both patient cohorts were representative of routine medical care delivered in academic, tertiary care settings, patients were matched by age and sex, and patients with prevalent DM2 were ascertained in both databases using similar, validated algorithms. Furthermore, while the findings of our study demonstrated that HIV-infected patients on PI-based regimens had a less robust glycemic response, increasing evidence suggests that newer agents in the PI class may not have the same adverse metabolic effects compared to older agents [51
]. While the majority of HIV-infected patients on PI-based regimens were on atazanavir/ritonavir and lopinavir/ritonavir (42.4% and 31.8%, respectively), given limitations in sample size, we were unable to evaluate the effect of individual PIs on glycemic control. Finally, the present study evaluated clinical care delivered at academic institutions and may not be generalizable to other settings.
In conclusion, HIV-infected patients in routine clinical care achieved smaller absolute reductions in HbA1c in response to initial diabetic medical therapy. Current guidelines on the management of DM2 in HIV-infected patients are based on established recommendations in the HIV-uninfected population [52
]. However, given the less robust glycemic response to initial diabetic therapy, optimizing medical therapy and achievement of target lipid and blood pressure goals may be even more critical in HIV-infected patients with DM2. Further research is needed to elucidate the mechanisms leading to this less robust glycemic response, including the contribution of specific PIs and chronic inflammation. Future studies should also evaluate optimal choice of pharmacologic therapy and the most accurate measurement of glycemia in this medically complex population, with the goal of decreasing the risk of clinical complications and mortality.